Background: The objective of this phase II trial wasto compare efficacy of Pmab plus FOLFIRI and Bmab plus FOLFIRI as second-line chemotherapy for patients (pts) with wild-type (WT) KRAS exon 2 mCRC, associated with comprehensive biomarker analysis. Methods: Pts with WT KRAS exon 2 mCRC refractory to first-line chemotherapy containing oxaliplatin and Bmab were randomly assigned to Pmab plus FOLFIRI or Bmab plus FOLFIRI. The primary endpoint was OS; secondary end points included PFS, ORR, safety and translational research. Results: Of 121 randomly assigned pts, 117 pts were eligible for analysis. OS was almost similar between two arms (HR, 1.16; 95% CI, 0.76 to 1.77) with median OS of 16.2 months in Pmab and 13.4 months in Bmab (Stratified Log-rank P=0.499). Median PFS was 6.0 months in Pmab and 5.9 months in Bmab (HR, 1.14; 95% CI, 0.78 to 1.66). ORR was 46.2% in Pmab and 5.7% in Bmab. KRAS, NRAS or BRAF mutations in circulating tumor DNA were identified in 19 (17.4%) of 109 pts whose baseline plasma samples were available for biomarker analysis. For pts with any of these mutations, Pmab showed worse OS than Bmab (HR, 0.42) meanwhile better trend was observed in Pmab for all WT (HR, 1.21; P for interaction =0.026). Pmab showed better OS than Bmab in patients with low serum VEGF-A (≤ median) level, (HR 1.92) while Bmab showed better OS among those with high level (HR 0.67; P for interaction=0.016, table). High serum levels of HGF, amphiregulin, EGF and Tenascin C were associated with worse OS among all pts. Conclusions: OS was almost similar with second-line FOLFIRI plus either Pmab or Bmab in pts with WT KRAS exon 2 mCRC. Oncogenic mutation in circulating tumor DNA and serum VEGF-A may be candidate biomarkers to stratify pts, which warrants further evaluation. Clinical trial information: UMIN000005216.